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Alveolar cell response to tracheal occlusion induced stretch in murine congenital diaphragmatic hernia hypoplastic lungs
Book - Dissertation
Fetal tracheal occlusion (TO) is a clinical therapy that has been proven to promote stretch-induced lung growth by blocking the fetal trachea and preventing the egress of lung fluid. TO is offered as a prenatal intervention for patients with severe lung hypoplasia due to congenital diaphragmatic hernia (CDH). This is a birth anomaly defect of the diaphragm that allows the abdominal contents to enter the chest during fetal life, leaving insufficient space for normal lung development. The subsequent pulmonary hypoplasia in turn leads to postnatal respiratory insufficiency and pulmonary hypertension. In this project, we plan to investigate the effect of stretch in normal and hypoplastic lung tissue on the progenitor cells that take part in fetal lung development, especially during the canalicular/saccular stages as this coincides with TO therapy in human fetuses. As it is still unknown how TO can lead to lung maturation in CDH patients at the molecular level, and this window of lung development involves the dynamic activities of multiple progenitors/epithelial cells of interest, it will be valuable to investigate whether TO-induced mechanical stretch might affect these cells specifically in CDH hypoplastic lungs. Because the impact of stretch on stem/progenitor cells has never been assessed in an in vivo setting before, performing fetal TO in a mouse model will deliver a rare opportunity to investigate its capability to alter the properties of stem/progenitor cells similarly to previously demonstrated in vitro studies. Also as insufficient lung growth remains a problem after clinical TO, therapies that target lung progenitor cell populations via these mechanotransduction pathways might help improve or replace TO as a CDH treatment.